Neonatal-Onset Congenital Ectropion Uveae May Be Caused by a Distinct CYP1B1 Pathologic Variant.

PURPOSE: To report underlying genetic variants of recently described distinct phenotype of newborn glaucoma: neonatal-onset congenital ectropion uveae (NO-CEU). DESIGN: Prospective cohort study. METHODS: Setting: tertiary care teaching institute. SUBJECTS: Thirteen children with clinical diagnosis of NO-CEU who had completed 1-year follow-up after glaucoma surgery and had undergone clinical exome sequencing (CES) by selective capture and sequencing of the protein-coding regions of the genes including 19 candidate genes for NO-CEU were assessed. The same criteria were applied for evaluating pathogenicity of variants to all the candidate genes. OUTCOME MEASURES: primary-genetic variants found on CES keeping in view the clinical indication of congenital glaucoma; secondary-corneal clarity and intraocular pressure (IOP) at baseline and 1-year follow-up, interventions required to control IOP, and postoperative visual acuity. The genetic variants were correlated with the outcome. RESULTS: All 13 patients diagnosed with NO-CEU had onset of glaucoma at birth and severe bilateral disease. Twelve of 13 (92.3%) patients harbored CYP1B1 variants. Nine of these 12 patients (83.3%) were homozygous for [c.1169G>A(p.Arg390His)] in exon-3 of CYP1B, with 5 common homozygous single-nucleotide polymorphisms flanking the pathogenic variant. They had intractable glaucoma and required multiple surgeries. Six patients had persistent corneal opacities, necessitating optical iridectomies. Three patients were compound heterozygous for CYP1B1 variants, showing [c.1169G>A(p.Arg390His)] along with [c.1103G>A(p.Arg368His)], [c.1103G>A (p.Arg368His)] along with [c.1403_1429dup(p.Arg468_Ser476dup)], and [(c.1063C>T(p.Arg355Ter)] along with [c.1325del(p.Pro442GlnfsTer15)]. These patients had better visual outcomes. CONCLUSIONS: NO-CEU appears to be a phenotypic marker for specific CYP1B1 genotypes, one of which is [c.1169G>A(p.Arg390His)] in our study population. Phenotype recognition is helpful to characterize the underlying genetic variants.

CDH1-related blepharocheilodontic syndrome is associated with diffuse gastric cancer risk.

We report the first case of diffuse gastric cancer in an individual with familial blepharocheilodontic syndrome (BCD) due to a germline CDH1 likely pathogenic variant. To date, other BCD affected relatives are nonpenetrant for diffuse gastric cancer posing challenges to counseling regarding gastric and breast cancer surveillance, and preventative total gastrectomy.

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

Clinical spectrum and pleiotropic nature of CDH1 germline mutations.

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer-the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype-phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin's pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome.

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

Newly identified paired box 6 mutation of variant familial aniridia: Congenital iris ectropion with foveal hypoplasia.

Congenital aniridia is a kind of eye disease characterized by complete or partial hypoplasia of the iris and is associated with other ocular anomalies including corneal opacity, glaucoma, and foveal hypoplasia. Heterozygous mutation of paired box 6 (PAX6) gene was identified in most cases of aniridia, with iatrogenic mutations accounting for about two-third of the cases and chromosomal rearrangements accounting for the other one-third. We report rare cases of variant aniridia, congenital iris ectropion associated with foveal hypoplasia in both a woman and her son with a mutation of PAX6 gene. To our knowledge, deletion c. 936delC in exon 8 of PAX6 gene has not been reported until now.

Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1.

PURPOSE: Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown. METHODS: We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families. RESULTS: We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype-phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation. CONCLUSION: Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.

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A newborn had a tight, dry skin with multiple fissures, an eclabium and ectropion. Breathing was compromised and regulation of body temperature was impaired. We described the patient as a 'collodion baby'. After genetic investigation the diagnosis congenital ichtyosis, recessive type 1 was made. At 12 months of age, the skin symptoms were significantly diminished.

Novel mutations in TGM1 and ABCA12 cause autosomal recessive congenital ichthyosis in five Saudi families.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a rare disorder of keratinization. Infants (10-15%) born with this condition are encapsulated in hyperkeratotic membrane covering the entire body and are called "collodion babies." So far, mutations in nine different genes have been identified as causative and implicated in the pathogenesis of the clinically and genetically heterogeneous group of ARCI disorders. Among these, TGM1 is the gene most commonly mutated in ARCI. METHODS: We identified 11 patients from five consanguineous but unrelated families affected by ARCI. These patients manifested thick adherent polygonal large scales all over the body. All six patients with TGM1 mutations were born with collodion membrane and had ectropion and eclabium, while none of the patients with ABCA12 mutations had these features. Molecular investigations were performed using the combined approach of homozygosity mapping and Sanger sequencing. RESULTS: Here we report two novel mutations c.397_398insAGTATGAGTA (p.Tyr136Ter); c.977-978delCT (p.Ser326Cysfs*8) in TGM1 in three different, unrelated Saudi families and one novel mutation c.6900C>A (p.Phe2300Leu) and one reported mutation c.3470C>T (p.Ser1157Leu) in the ABCA12 gene in two unrelated Saudi families with ARCI. CONCLUSIONS: The identification of these homozygous variants using combined approaches of homozygosity mapping with direct sequencing are the disease causing mutations in these families. Furthermore, these findings are essential for the genetic diagnostic and prognostic workup with ARCI in Saudi patients.

Genotype and Anterior Segment Phenotype in a Cohort of Turkish Patients with Lamellar Ichthyosis.

PURPOSE: To evaluate the ocular surface and topography findings of lamellar ichthyosis, and to investigate the correlation of these findings with mutations in TGM1, CYP4F22 and NIPAL4 genes. METHODS: Twelve patients with lamellar ichthyosis were evaluated. Routine ophthalmic examination including Schirmer 1, tear break-up time and ocular surface staining score, topography, and genetic evaluation for coding exons of TGM1, NIPAL4 and CYP4F22 genes were performed. RESULTS: The mean age of the patients was 19.75 ± 9.15 (range, 4-31) years. Mean Schirmer 1 scores of the right and the left eyes were similar (18.75 ± 3.10 mm). Mean tear break-up time of the right and the left eyes were 6.58 ± 2.74, 6.58 ± 3.02 seconds, respectively. Mean ocular surface staining grade was 0.36 ± 0.20 in the right, and 0.39 ± 0.17 in the left eyes. Keratoconus was detected in two patients. Two patients with bilateral cataract formation were found. Genetic sequencing revealed that one case had homozygous R326X mutation in the CYP4F22 gene, two cases had homozygous A176D mutation in the NIPAL4 gene, and three had homozygous M1T mutation in the same gene. Mutations were detected in patients with keratoconus and in a patient with bilateral cataract formation. CONCLUSIONS: In lamellar ichthyosis, eyelid malformations together with decreased tear break-up time might cause sight-threatening complications. Genetic counseling for mutations might enable the physician to predict the possibility of upcoming ocular problems in lamellar ichthyosis patients.